Bronchopulmonary dysplasia (BPD) is a developmental chronic lung disease that occurs mainly in premature infants due to respiratory failure or ventilator treatment due to this, and as ultra-small premature babies having a birth weight of less than 1,000 gm who have a much higher risk of the onset of BPD due to, particularly, a more severe degree of immaturity of the lungs have recently been actively treated, the incidence frequency of BPD is rapidly increasing. BPD is a main cause of neonatal death, particularly premature infants, results in an extended period of hospitalization in the case of surviving infants, and causes severe sequelae such as pulmonary hypertension or 50% or more of the cases that require re-hospitalization due to viral acute bronchiolitis, pneumonia, and the like even after leaving the hospital. In addition, there are many cases in which BPD is converted into bronchial asthma due to increased bronchial hypersensitiveness for a long-term period, and BPD is known to be ultimately associated with severe neurologic sequelae such as cerebral palsy.
Conventionally, as a method of treating BPD of premature infants, physical efforts have been mainly made to try to perform treatment by reducing pressure, volume damage, and oxygen concentration by positive pressure ventilation in treatment of artificial ventilation of neonates and premature infants, and a steroid therapy for reducing damaged lung inflammation is used together, but when this treatment is used in premature infants, it has been reported to be associated with an increase in neurologically poor prognoses, especially cerebral palsy, and thus the use thereof is limited. Therefore, there is a very urgent need to develop an effective and distinct therapy for BPD of neonates/premature infants due to intractability thereof.
Mesenchymal stem cells are known to have multipotentiality and be involved in regeneration, treatment, and immune responses of tissues, and thus efforts have been made to develop a therapeutic agent for chronic pulmonary disease such as BPD by isolating and culturing mesenchymal stem cells from umbilical cord blood, bone marrow, and the like using these characteristics. However, these therapeutic agents using stem cells themselves have the following limitations and side effects.
First, cell therapeutic agents basically have the possibility of tumorigenicity due to DNA transfer.
Second, stem cells may cause a vascular obstruction or a cardiac infarction due to big sizes thereof (see Circ Heart Fail. 2010; 3; e5-e6).
Third, there is a problem of rejection due to a cell surface antigen when transplantation (allotransplantation) is performed using allogenic cells such as cord blood.
Fourth, generally, manufacturing processes of cell therapeutic agents are complicated and there are many limitations in storage and transportation thereof, thus increasing manufacturing costs.
As such, due to the fundamental limitations of stem cells, methods of improving efficacy using genetic modifications have been developed as methods for reducing side effects and enhancing therapeutic effects, but there are no clear alternatives to date.
Meanwhile, exosomes are small vesicles (approximately 30 nm to 100 nm in diameter) having a membranous structure secreted from various cells, and according to studies using an electron microscope, exosomes were observed to originate from intracellular specific compartments, which are called multivesicular bodies (MVBs), rather than being directly detached from a plasma membrane and to be released and secreted out of cells. That is, when the fusion of MVBs and a plasma membrane occurs, vesicles are released into the extracellular environment, which are called exosomes. Although it has not been clearly discovered how these exosomes are created by a molecular mechanism, it has been known that various types of immune cells including red blood cells, B-lymphocytes, T-lymphocytes, dendritic cells, platelets, macrophages, and the like, tumor cells, stem cells, and the like also produce and secrete exosomes when alive.
In particular, it is known that exosomes derived from stem cells contain nuclear components as well as receptors and proteins, and thus play a role in intercellular communication. In addition, the exosomes derived from stem cells contain relatively less animal serum than stem cells, and thus also have no risk of zoonosis due to infection of animal serum. When considering these properties of exosomes, a cell therapeutic agent using exosomes is expected to be a new paradigm capable of overcoming the limitations of existing stem cell therapies.